The electrocardiogram (ECG) is based on the electrical activity of the heart muscle cells. In the resting stage, the inside of the cardiac cells has a negative charge compared to the outside of the cells. The resulting voltage difference between the internal and the external spaces of the cell membrane is called transmembrane potential. The discharging of this voltage is known as depolarization and is associated with the start of the contraction of the heart muscle cell fibers. After contraction of the ventricles, the heart muscle cells redevelop substantially the same voltage over the cell membrane. This recovery phase is called the repolarization process of the heart ventricles. An ECG measured from the skin surface measures a total electrical component created by the depolarization and repolarization of the heart's muscular cells.
The repolarization of the heart is made possible in part by ion channels within the myocardial cells of the heart which allow an ion current to redistribute charge. It is highly important that the regulation of the ion currents during the ventricular repolarization process occurs without interference, since a delay in this process or any other abnormalities can lead to a substantially increased risk for sudden cardiac death.
Medical professionals have used electrocardiograms (ECG's) to examine the ventricular repolarization period, also known as the QT interval, to check for elongation of the QT interval. In general, an elongated QT interval may be considered to be indicative of a delay in the ventricular repolarization process. While medications in some cases may be the cause of an elongated QT interval, for many people are predisposed to have an elongated QT interval due to one or more congenital mutations. Those patients having a congenital predisposition for an elongated QT interval are referred-to as having Long QT Syndrome, or LQTS. The clinical course and the precipitating risk factors in the congenital Long QT Syndrome (LQTS) are genotype specific. Among LQTS mutations, KvLQT1 (LQT1) and HERG (LQT2) mutations have the higher likelihood of recurrent cardiac events and their diagnosis is crucial to reduce lethal outcome.
The Long QT Syndrome (LQTS) is an inherited disease caused by genetically determined defects in trans-membrane ion channel subunit. LQTS patients are at high risk of sudden cardiac death due to the development of ventricular tachycardia degenerating in ventricular fibrillation and cardiac arrest. The prevalence of the syndrome may be expected to occur in 1 in 3000-5000 individuals per year in the United States. The number of cases of sudden cardiac death associated with the LQTS is unknown but among the 300,000 sudden cardiac deaths documented each year, one may expect around 2-5% having LQTS-related arrhythmic death. In the US, the syndrome remains an under diagnosed disorder because an estimated 10 to 15% of the LQTS gene carrier patients have a QT interval duration near normal values.
Seven mutant genes have been associated with LQTS: KvLQT1/minK, HERG, SCN5A, Ankyrin B, KCNE1, KCNE2 and KCNJ2. Most of these genes encode cardiac ion channels and their mutation leads to dysfunction of the ion current kinetics. Among the current 150 mutations identified in the seven LQTS genes, LQT1 and LQT2 represent the majority of cases (88%) whereas LQT3 account for (7%) and the others are very rare. Typically in these types of LQTS, the arrhythmias occur in conjunction with vigorous physical exercise and emotional stress. The mutation of the HERG (LQT2) gene decreases the rapidly activating delayed rectifier potassium (K+) current (IKr). KvLQT1 mutation (LQT1) is associated with blockade of the slowly activating delayed rectifier K+ currents (IKs). The inhibition of IKr/IKs ion currents is associated with a prolongation of the action potentials within the heart leading in general to a prolonged QT interval on the surface ECGs.
Once a patient is identified as having an elongated QT interval, there is still a clinical need for discriminating mutation-specific syndrome (LQT1 vs. LQT2 patients) because of the mutation-specific therapeutic strategies one may consider. In this case, the QT/QTc prolongation is not a useful marker, the QT interval is, in average, prolonged similarly within the two groups. Traditionally, genetic testing has been prescribed to determine which form of Long QT Syndrome is the cause. Unfortunately, genetic testing can cost thousands of dollars and is time consuming. The expense of the testing alone prevents many patients from receiving important information about the root cause of their elongated repolarization interval. Therefore, there exists a need for an economical, reliable, and quicker way to differentiate between patients with the LQT1 and LQT2 mutation.